title: Molecular basis for the regulation of the H3K4 methyltransferase activity of PRDM9.
abstract: PRDM9, a histone lysine methyltransferase, is a key determinant of the localization of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. Here, we report the crystal structure of the PRDM9 methyltransferase domain in complex with a histone H3 peptide dimethylated on lysine 4 (H3K4me2) and S-adenosylhomocysteine (AdoHcy), which provides insights into the methyltransferase activity of PRDM proteins. We show that the genuine substrate of PRDM9 is histone H3 lysine 4 (H3K4) and that the enzyme possesses mono-, di-, and trimethylation activities. We also determined the crystal structure of PRDM9 in its autoinhibited state, which revealed a rearrangement of the substrate and cofactor binding sites by a concerted action of the pre-SET and post-SET domains, providing important insights into the regulatory mechanisms of histone lysine methyltransferase activity.
authors.affiliation: Structural Genomics Consortium, University of Toronto, MaRS Center, South Tower, 7(th) Floor, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Nikolas
authors.initials: N
authors.lastname: Mathioudakis
authors.forename: Boubou
authors.initials: B
authors.lastname: Diagouraga
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.forename: Ludmila
authors.initials: L
authors.lastname: Dombrovski
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baudat
authors.forename: Stephen
authors.initials: S
authors.lastname: Cusack
authors.forename: Bernard
authors.initials: B
authors.lastname: de Massy
authors.forename: Jan
authors.initials: J
authors.lastname: Kadlec
mesh_terms: D000595:Amino Acid Sequence; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013379:Substrate Specificity
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human